Oral ingestion of water greatly elevates blood pressure in individuals with impaired autonomic reflexes. While the effect averages 30-40 mmHg, there is large interindividual variation with occasional increases of 100 mmHg. We were initially startled by the magnitude of this response, but others have now replicated it and confirmed its magnitude. An effect is also found in treated hypertensive subjects and in normal subjects, albeit it at smaller magnitude. We have also found that ingestion of water potentiates the effect of the pressor drug phenylpropanolamine (PPA). In view of its magnitude and robustness, the pressor response to water may signal an important but heretofore unrecognized mechanism at work in human cardiovascular regulation both in health and disease. The water response may have important diagnostic and therapeutic implications. In particular, it may be the major unrecognized determinant of noise in blood pressure assessment in the older population, and might possibly be a source of interindividual and intraindividual variation in orthostatic tolerance. The purpose of this proposal is to address the mechanism of the cardiovascular effect of water ingestion, and address the basis of interindividual variation in this gastropressor response. We seek to understand if the sympathetic nervous system is mediating water's pressor response in Specific Aim 1. In Specific Aim 2, we try to determine the macroscopic stimulus underlying the response. In Specific Aims 3 and 4, we address potential efferent mechanisms at a more molecular level in both human subjects and in a mouse model system. Finally in Specific Aim 5 we try to determine the basis of the age dependency of the pressor response to water. Although water is a part of daily life, we believe the gastropressor response we have observed may have important consequences in health and disease.